Major depression is a serious health problem affecting more than 5% of the population, with a life-time prevalence of 15-20%.
Selective serotonin reuptake inhibitors have produced success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in fewer than two-thirds of patients.
Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long-term treatment is required before clinical improvement is achieved.
It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5HT1A receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants.
A 5HT1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism (Perez, V., et al., The Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5HT1A receptor.
In accordance with this invention, there is provided a group of novel compounds of the formula: 
wherein
R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2, R3, R4, R5 and R7 are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms
R6 is hydrogen or alkyl of 1 to 6 carbon atoms;
A dotted line represents an optional double bond;
A and D are selected from carbon substituted by R1 and nitrogen, provided that at least one of A and D is nitrogen;
E and G are carbon, substituted by R1;
Z is N or CR7; and
n is an integer 0, 1 or 2; or pharmaceutically acceptable salts thereof.
A is preferably nitrogen.
R1 is preferably hydrogen, hydroxy, halo, alkyl of 1 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms. More preferably, R1 is hydrogen, alkyl of 1 to 3 carbon atoms or amino. In still more preferred embodiments of the present invention R1 is substituted at the 8-position of the 2,3-dihydro-1,4-dioxino[2,3-f] quinoline system.
R2 is preferably hydrogen, hydroxy, halogen, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of one to six carbon atoms. In still more preferred embodiments of the present invention R2 is hydrogen, halogen or alkoxy of 1 to 6 carbon atoms. In still more preferred embodiments of the present invention R2 is hydrogen.
R3, R4, R5 and R7 are preferably independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. In still more preferred embodiments of the present invention R3, R4, R5 and R7 are preferably independently selected from hydrogen, cyano or halogen.
R6 is preferably hydrogen. Preferably n is 0 or 1. More preferably n is 0.
In still other preferred embodiments of the invention R2 and R6 are hydrogen, one of R3, R4, R5 and R7 is hydrogen, halogen or cyano, n is 0 and the dotted line represents a double bond.
In other preferred embodiments of the invention is provided compounds of Formula Ia. 
wherein R1, R2, R3, R4, n, Z and the dotted line are as described above.
This invention relates to both the R and S stereoisomers of the aminomethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinolines, as well as to mixtures of the R and S stereoisomers. Throughout this application, the name of the product of this invention, where the absolute configuration of the aminomethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinolines is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two. In some embodiments of the present invention the S stereoisomer is preferred.
Where a stereoisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. xe2x80x9cSubstantially freexe2x80x9d, as used herein, means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
It is further recognized that tautomers of the claimed compounds may exist; for instance, when R1 is hydroxy, a tautomeric form may exist. The present invention thus encompasses tautomeric forms of compounds of the present invention.
Alkyl, as used herein, refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
Alkanamido, as used herein, refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanoyloxy, as used herein, refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanesulfonamido, as used herein, refers to the group Rxe2x80x94S(O)2xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Alkoxy, as used herein, refers to the group Rxe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Carboxamido, as used herein, refers to the group NH2xe2x80x94C(xe2x95x90O)xe2x80x94.
Carboalkoxy as used herein refers to the group Rxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Halogen (or halo) as used herein refers to chlorine, bromine, fluorine and iodine.
Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
Specific examples of compounds of Formula I are:
2-[4-(5-Methoxy-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
[4-(5-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-2,3-dihydro[1,4]-dioxino[2,3-f]quinoline;
2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
3-[1-(2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-1,2,3,6-tetra-hydropyridin-4-yl]-1H-indole-5-carbonitrile;
3-[1-(2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-1,2,3,6-tetra-hydropyridin-4-yl]-1H-indole-5-carboxylic acid amide;
2-[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl-methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-({4-[(5-Fluoro-1H-indol-3-yl)methyl]piperidin-1-yl}methyl)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(6-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(1H-Indol-3-yl)piperidin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinoline;
8-Ethyl-2-[(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
8-Ethyl-2-[(4-(5-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
6-Fluoro-2-[(4-(5-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
6-Fluoro-2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-6-methoxy-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-8-ylamine;
2-({4-[(7-Ethyl-1H-indol-3-yl)methyl]piperidin-1-yl}methyl)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
2-({4-[(6-Chloro-1H-indol-3-yl)methyl]piperidin-1-yl}methyl)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
2-[4-(7-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline
2-[4-(5-Methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;
2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-9-methyl-2,3-dihyrdo[1,4]dioxino[2,3-f]quinoline, and
8-Ethyl-2-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; and pharmaceutically acceptable salts thereof.
Further in accordance with the present invention are provided compounds of Formula II 
wherein
R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
X is halogen, hydroxy, alkylsulfonate of 1 to 6 carbon atoms, trifluoromethanesulfonate or benzenesulfonate, in which the benzene ring is optionally substituted with halogen, nitro, trifluoromethyl, cyano, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
Specific examples of compounds of Formula II are
2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate;
(8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl 4-methylbenzenesulfonate;
(8-Ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl 4-methylbenzenesulfonate;
6-Fluoro-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate;
6-Methoxy-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate;
(8-Amino-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl 4-methylbenzenesulfonate; and
9-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl 4-methylbenzene sulfonate.
Compounds of Formula II are particularly useful for the production of compounds of Formula Ia.
Compounds of the present invention are prepared in accordance with the following general description and specific examples. Variables used are as defined for Formula I, unless otherwise noted.
The 2-azaheterocyclylmethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinolines in which R1 is H are prepared as illustrated in Scheme I. Specifically, the appropriately substituted nitroguaiacol (1) is alkylated with allyl bromide in the presence of a suitable base such as sodium hydride to produce (2) and then demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenol (3) is then alkylated with glycidyl 
tosylate or an epihalohydrin in the presence of a base such as sodium hydride to produce (4) and heated in a high boiling solvent such as mesitylene or xylene to effect both rearrangement of the allyl group and cyclization to the dioxan ring. The resulting primary alcohol (5) is converted to the tosylate by reaction with p-toluenesulfonyl chloride in the presence of a tertiary amine or alternatively to a halide by reaction with carbon tetrabromide or carbon tetrachloride in combination with triphenylphosphine. The allyl side chain is then isomerized by treatment with catalytic bis-acetonitrile palladium (II) chloride in refluxing methylene chloride or benzene to produce (6). Allylic oxidation with selenium dioxide in refluxing dioxane/water gives the o-nitrocinnamaldehyde, which upon reduction with iron in acetic acid cyclizes to the 2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyl-tosylate or halide (7). Replacement of the tosylate or halide with the appropriately substituted azaheterocycle in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of Formula Ia.
Compounds of the invention in which R1 is alkyl may be prepared from the nitro olefin described in Scheme I in the manner described in Scheme II. The rearranged olefin (6) is treated sequentially with ozone and a tertiary amine or with osmium tetroxide and sodium periodate to give the o-nitrobenzaldehyde (8). 
Condensation with the appropriate triphenylphosphoranylidene ketone under Wittig conditions gives the o-nitrostyryl ketone (9), which upon reduction by iron in acetic acid, cyclizes to the corresponding 2,3-dihydro-1,4-dioxino[2,3-f]-quinoline-2-methyltosylate (10). Replacement of the tosylate with the appropriately substituted azaheterocycle as above gives the title compounds of the invention.
Substitution of trimethyl phosphonoacetate for the triphenylphosphoranylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (II) chloride and cyclization in acid gives the compounds of the invention in which R1 is hydroxy. Alkylation of this hydroxy derivative by a suitable alkyl halide or tosylate in the presence of base gives the compounds of the invention in which R1 is alkoxy. Treatment of the hydroxy derivative with an inorganic acid chloride such as phosphoryl chloride or bromide gives the compounds of the invention in which R1 is halo. Substitution of diethyl cyanomethylphosphonate for the triphenyl-phosphoranylidene ketone in the Wittig procedure above, followed by reduction of the nitro group with tin (II) chloride and cyclization in acid gives the compounds of the invention in which R1 is amino.
The o-nitrobenzaldehyde (8) used in the Wittig chemistry described in Scheme II may be alternatively prepared as shown in Scheme III. The appropriate mono-allylated catechol (11) is elaborated with glycidyl tosylate as described above to produce (12) and rearranged in refluxing mesitylene. Cyclization to the benzodioxan methanol is 
effected by treatment with sodium bicarbonate in ethanol and the alcohol (13) is converted to the tosylate or halide (14) as described in Scheme (I). After rearrangement of the double bond by treatment with catalytic bis-acetonitrile palladium chloride in refluxing methylene chloride to produce and cleavage with ozone or osmium tetroxide/sodium periodate as described above, the resulting aldehyde (15) is regioselectively nitrated with a combination of nitric acid and tin (IV) chloride to produce (8).
Compounds of the invention in which R2 is attached to position 6 of the 2,3-dihydro-1,4-dioxino[2,3-f]quinoline may be alternatively prepared by a variation of the Skraup quinoline synthesis according to Scheme IV. The appropriately substituted benzodioxan methyltosylate (16) is nitrated under standard conditions with nitric acid in a solvent such as dichloroethane and the resulting nitro compound (17) 
reduced by treatment with hydrogen in the presence of a catalyst such as platinum on sulfide carbon. Treatment of the resulting aniline (18) with acrolein in the presence of hydrogen chloride and an oxidant such as p-chloranil or naphthoquinone gives the corresponding 2,3-dihydro-1,4-dioxino[2,3-f]quinoline (19). Replacement of the tosylate with the appropriately substituted azaheterocycle as above gives the title compounds of the invention.
The guaiacols, catechols, benzodioxan methyltosylates and azaheterocycles appropriate to the above chemistry are known compounds or can be prepared by one schooled in the art.
In yet another method, compounds of the present invention may be prepared in accordance with Scheme V. 
The synthesis of compound I is comprised of steps that begin with halogenation of 20 where Rxe2x80x2 is alkyl of 1-6 carbon atoms, with reagents such as N-halosuccinimide in acetonitrile to give 21 (where Hal is halogen such as Br, Cl or I). Deprotecting 21 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, or trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl gives the salt 22. Free base 22 may be obtained by neutralization with an Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol.
Alkylation of 22, either as the free base or as the salt, with benzyl or substituted benzyl protected glycidyl ethers 
where Rxe2x80x3 is benzyl, substituted benzyl such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxybenzyl) in suitable polar solvents such as DMSO, DMF, or DMA in the presence of bases such as sodium carbonate, potassium carbonate, or triethylamine gives 23.23 was then cyclized using palladium catalysts such as tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate with ligands from the group consisting of (xc2x1) BINAP and separate enantiomers thereof, (xc2x1) Tol-BINAP and separate enantiomers thereof; 1-1xe2x80x2-bis(diphenylphosphino) ferrocene, 1,3-bis(diphenylphosphino)propane, and 1,2 bis(diphenyl-phosphino)ethane in the presence of bases such as NaH, LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium t-butoxide or potassium phosphate tribasic in suitable solvent such as toluene, or alternatively, with copper catalyst such as copper iodide in the presence of bases such NaH, LiH, KH in a suitable solvent such as toluene to afford 24.
Deprotection of quinoline 24 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl or under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate gives quinaldine 25. The hydroxyl moiety of 25 can be activated with sulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfonyl chloride in the presence of bases such as triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or toluene to afford 26 where Rxe2x80x2xe2x80x3 is sulfonate such as p-toluenesulfonate, methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or 4-bromobenzenesulfonate. The final coupling of 26 with azaheterocycles appropriate to the invention, in the presence of bases such as Hxc3xcnig""s base (diisopropyl ethylamine), potassium carbonate, or sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF, or DMA affords final compound I.
The compounds of the invention may be resolved into their enantiomers by conventional methods or, preferably, the individual enantiomers may be prepared directly by substitution of (2R)-(xe2x88x92)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate in the procedures above.
A protocol similar to that used by Cheetham et. al. (Neuropharmacol. 32:737, 1993) was used to determine the affinity of the compounds of the invention for the serotonin transporter. The compound""s ability to displace 3H-paroxetine from male rat frontal cortical membranes was determined using a Tom Tech filtration device to separate bound from free 3H-paroxetine and a Wallac 1205 Beta Plate(copyright) counter to quantitate bound radioactivity. Ki""s thus determined for standard clinical antidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and 67.6 nM for zimelidine. A strong correlation has been found between 3H-paroxetine binding in rat frontal cortex and 3H-serotonin uptake inhibition.
High affinity for the serotonin 5HT1A receptor was established by testing the claimed compound""s ability to displace [3H] 8-OH-DPAT (dipropylamino-tetralin) from the 5HT1A serotonin receptor following a modification of the procedure of Hall et al., J. Neurochem. 44, 1685 (1985) which utilizes CHO cells stably transfected with human 5HT1A receptors. The 5HT1A affinities for the compounds of the invention are reported below as Ki""s.
Antagonist activity at 5HT1A receptors was established by using a 35S-GTPxcex3S binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 109: 1120, 1993), in which the test compound""s ability to affect the binding of 35S-GTPxcex3S to membranes containing cloned human 5HT1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OH-DPAT. The test compound""s maximum inhibitory effect is represented as the Imax, while its potency is defined by the IC50.
The results of the three standard experimental test procedures described in the preceding three paragraphs were as follows:
Like the antidepressants fluoxetine, paroxetine and sertraline, the compounds of this invention have the ability to potently block the reuptake of the brain neurotransmitter serotonin. They are thus useful for the treatment of diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), and related illnesses. Moreover, the compounds of this invention have potent affinity for and antagonist activity at brain 5HT1A serotonin receptors. Recent clinical trials employing drug mixtures (eg, fluoxetine and pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment combining SSRI activity and 5HT1A antagonism (Blier and Bergeron, 1995; F. Artigas et. al., 1996; M. B. Tome et. al., 1997). The compounds of the invention are thus exceedingly interesting and useful for treating depressive illnesses.
Thus the present invention provides methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.
Also encompassed by the present invention are pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of Formula I, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a xe2x80x9ctherapeutically effective amount.xe2x80x9d The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the human.
Provide, as used herein, means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
The present invention includes prodrugs of compounds of Formula I and Ia. Prodrug, as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). xe2x80x9cDesign and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
The following examples illustrate the production of representative compounds of this invention.